We have shown previously that a combination of inophore A23187 and calcium induced marked morphological changes in the structure of cultured hepatocytes as seen by scanning electron microscopy (SEM). We have extended our observations on these structural changes by utilizing transmission electron microscopy (TEM). The numerous balloons and blebs observed when cells were treated with calcium ionophore A23187 in the presence of calcium primarly involved the plasma membrane; blebs contained only a pale matrix largely deboid of cytoplasmic organelles. The major cell organelles appeared intact although damaged cells exhibit swollen mitochondria. Comparison with the toxicity induced by 2,4-dinitropohenol (DNP) indicated that although ionophore and calcium cause some uncoupling of oxidative phosphorylation and hence decreased ATP levels, this action is not sufficient to account for the observed toxicity.